Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

• Published in: Pharmaceutical research Vol. 37; no. 12; p. 250
• Main Authors: Britz, Hannah, Hanke, Nina, Taub, Mitchell E., Wang, Ting, Prasad, Bhagwat, Fernandez, Éric, Stopfer, Peter, Nock, Valerie, Lehr, Thorsten
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2020; Springer; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Comparative analysis; Complications and side effects; Drug dependence; Drug interaction; Drug interactions; Furosemide; Intravenous administration; Medical Law; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Plasma; Probenecid; Research Paper; Rifampin; probenecid; drug-drug interaction (DDI); furosemide; organic anion transporter (OAT); physiologically based pharmacokinetic modeling (PBPK)
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-020-02964-z

Purpose
To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling.
Methods
PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (C
max
) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies.
Results
The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI C
max
ratios within 1.25-fold of the observed values, and all predicted DDI AUC and C
max
ratios within 2.0-fold.
Conclusions
Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.